Characterization, epidemiology and risk factors of multiple drug allergy syndrome and multiple drug intolerance syndrome: A systematic review

Abstract Background Multiple drug allergy and multiple drug intolerance syndrome (MDAS/MDIS) labels are an impediment to clinical care and knowledge regarding these conditions is limited. This systematic review investigated the characterization, epidemiology, risk factors, clinical impact and pharmaco‐economics of MDAS and MDIS. Methods Systematic literature search across 11 databases (01 January 2000–06 November 2020) for MDIS, MDAS and related terminology. Studies were reviewed for quality of evidence and risk of bias by employing Critical Appraisal Skills Programme cohort study checklist. A narrative synthesis approach facilitated by systematic textual descriptions, tabulation and thematic analysis was adopted. Results There was heterogeneity in terminology and methodology. Few studies applied standard drug allergy diagnostic methods. There is some evidence to suggest that multiple drug hypersensitivity syndrome (MDHS; i.e., confirmed allergies in MDAS) is a distinct clinical entity. Prevalence of MDIS and MDAS labels in unselected & selected populations varied between 2.1%–6.4% & 4.9%–90% and 1.2% & 0%–36% respectively. Reported risk factors included female gender, increasing age, body mass index, anxiety, depression, co‐morbidities, concurrent allergies and increased healthcare utilization. Drugs commonly implicated were antibiotics and non‐steroidal anti‐inflammatory drugs. No studies relating to clinical impact and pharmaco‐economics were found. Conclusion There is considerable burden of MDAS and MDIS labels. Data needs cautious interpretation as majority of studies described involved unverified labels. Despite this limitation and heterogeneity of studies, there is some evidence to suggest that MDHS is a distinct clinical entity. Well‐designed multi‐centre studies applying standardized terminology and diagnostic methodology are needed to gain further insight into these conditions.


| INTRODUCTION
Adverse drug reactions (ADRs) are a response to a medicine that is noxious and unintended 1 and are broadly classified into two types.
Type A reactions are an exaggerated response to a drug's normal pharmacological action when administered at the standard therapeutic dose. 1 Drug allergy (type B ADR), is a terminology that is employed in the context of a 'true' hypersensitivity reaction (HSR) as per Gell and Coombs classification and is usually a Type-1 (immediate or IgE mediated) or Type-4 (non-immediate or T cell mediated) HSR. [2][3][4][5] Skin tests are useful in the investigation of Type-1 and Type-4 HSRs. 6 Drug intolerance is not immunologically mediated and may be pseudo-allergic or idiosyncratic. 2,3 A drug reaction is less likely to have an allergic basis in the absence of histamine-mediated symptoms or systemic involvement, and if it is characterized by nonspecific symptoms or if isolated gastrointestinal symptoms are reported. 4,5 Mechanisms underpinning drug intolerance are poorly understood. 2,5 It is the least specific term for an ADR and may be added into a health record to avoid subsequent use of a drug.
Drug intolerances are commonly mislabelled as an 'allergy' in patient records. Inaccurate drug allergy labelling has been extensively studied in high income countries (HICs) in the context of penicillin allergy labels. Between 90% and 95% of penicillin allergy labels are inaccurate, leading to prescription of expensive broadspectrum antibiotics which enhance risk of antimicrobial resistance, Clostridioides difficile infection, surgical site infections, lengthen hospital stay and increase healthcare costs. [7][8][9] Reported penicillin allergy, with or without multiple drug intolerance (MDI) syndrome has been shown to increase healthcare utilization with an increase in number of visits per follow-up. 8 Poor documentation and knowledge gaps amongst healthcare professionals have been linked to inaccurate penicillin allergy labelling. [10][11][12][13] Multiple drug allergy syndrome (MDAS) refers to patients describing symptoms suggestive of a HSR to ≥1 drug class. Multiple drug intolerance syndrome (MDIS) on the other hand refers to patients describing ADRs suggestive of a non-immunological reaction to ≥3 drug classes. Given the unmet need of specialist allergy services globally, limitations and onerous nature of drug allergy tests, MDAS and MDIS labels are an impediment to healthcare delivery, particularly in the context of antimicrobial stewardship. 14,15 The main aim of this study was to systematically review pub- cohort stud* OR cohort analys* OR cross-sectional stud* OR cross sectional analys* OR observational analys* OR prevalence OR disease frequency OR incidence OR rate). Search terms were agreed and refined by reviewers (PJ, SA, JM, TK) after an initial scoping exercise.
The systematic review protocol was registered with PROSPERO (CRD CRD42022302225), an international prospective register of systematic reviews based at the University of York Centre for Reviews and Dissemination. 16 Whilst the primary aim of our systematic review was to investigate MDAS and MDIS, this study also included closely related conditions as identified in the literature search including MDH, multiple drug hypersensitivity syndrome (MDHS), MDI, multiple antibiotic sensitivity syndrome (MASS) and polyallergy (PA). Abstract only publications, conference presentations, letters, grey literature, reviews, and meta-analyses were excluded. The report was structured using the Preferred Reporting Items for Systematic Reviews (PRISMA). 17 A total of 10,728 records across all databases were exported to the reference management tool 'Endnote'. Removal of duplicates resulted in 7041 title and abstract records being screened by the first reviewer (PJ) who then applied the exclusion criteria to remove 7023 records. The second reviewer (SA) reviewed 10% of the excluded records and there was consensus for the exclusions.
Eighteen records were assessed for eligibility. One further study was identified for review from bibliographies. Full text review of 19 studies was carried out independently by two reviewers (PJ and SA). Third (TK) and fourth (JM) reviewers provided a consensus opinion with agreement that the 19 studies were suitable for the systematic review. Studies were reviewed for quality of evidence and risk of bias by applying the Critical Appraisal Skills Programme cohort study checklist. 18 This method was chosen due to methodological heterogeneity of the studies reviewed. A systematic narrative synthesis facilitated by systematic textual descriptions, tabulation and thematic analysis was adopted due to the heterogeneity of studies.
Quality assessment of basic drug allergy work up was conducted by comparing to British and European guidelines. 4 (Tables 1-3)

| Definitions and diagnosis
The systematic review revealed multiple nomenclature in the context of patients presenting with an allergy or intolerance to multiple drugs. This was based on the number of drugs involved, whether they were different drugs or from unrelated drug classes and if the patient was 'truly' allergic based on a systematic assessment involving a clinical history, allergy testing and/or a DPT when deemed appropriate. Table 1 lists acronyms along with respective definitions used   in previous studies. MDAS was referred to as a reaction to ˃1 different drug class in one study 26 and as an allergy to ≥2 in one study. 30 One study did not specify number of drug classes and used the term 'multiple drug intolerance' interchangeably with MDAS. 31 MDIS referred to as ADR/HSR/intolerance to ≥3 drug classes in five studies, 27,30,32,40,42 and to ≥3 drugs by Omer et al. 25 MDI was referred to as ADR/intolerance to ≥3 drug classes in two studies. 28,42 MDH or MDHS was referred as HSR/allergy to ≥2 drug classes in six studies. 29,[33][34][35][36]41 MASS was referred to as sensitivity to ˃1 drug class in one study. 37 PA was referred to as an ADR to ≥3 drugs in a single study. 38

| Diagnosis of respective condition
The proportion of patients diagnosed with MDAS, MDIS and other related conditions in unselected and selected (i.e. those with a suspected allergy/ADR/HSR) populations in different settings showed variation. MDAS diagnosis was reported in a secondary care unselected population as 1.2% 26 and ranged from 0%, 42 23%, 29  (suspected HSR) and 23.3% 39 (suspected ADR) to all seven patients in a small suspected allergy cohort. 38 MDHS diagnosis in a larger secondary care suspected allergy population was reported as 2.5%. 41 All selected populations were in secondary care (MDAS, 28,29,42 MDIS, 25

| Common drugs implicated
A variety of drugs were implicated, but most common were antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs). Whilst some studies focussed on specific drug groups only (anti-hypertensives 20,34 and antibiotics 29,41 ), the majority found a range of drugs to be involved including anti-epileptics, opioids, angiotensin converting enzyme inhibitors, corticosteroids and psychotropics. 12 out of 19 studies (63%) implicated penicillin allergy. 25,26,29,30,33,[35][36][37][38][39][40][41] Studies with larger patient numbers (>250 patients) 26,30,[36][37][38][39]41,42 and those including drug allergy workup 26,29,33,36,37,41 identified greater numbers of drug classes. These were a mixture of retrospective reviews of patient records and prospective studies, the majority were carried out in HICs.  'simultaneous' (during the same episode) and 'sequential' (during separate occasions) MDH in the context of SCARS and DRESS syndrome has also been reported. 35,38 There is also some evidence for a role for persistent T-cell activation involving a subset of CD4 + CD25 dim , CD38 + , and PD-1 + T cells in MDHS. [45][46][47] It is however unclear if MDIS is a distinct clinical syndrome, as it is a clinical diagnosis based on subjective and varied symptomatology without an immunological basis and with no confirmatory in vivo or in vitro tests.

| Risk factors
This systematic review process was robust, addressed the study research aims and adhered to PRISMA guidelines. 48 The review spanned over 2 decades with no language limitations and used wide search terms. There were however multiple limitations in pub-